Summary: The NHGRI intramural program has expanded research efforts to modify and transplant adult hematopoietc stem cells (HSC) to combat HIV infection. The HSC is the ultimate progenitor of all peripheral blood cells, including the CD4+ lymphocytes that are infected by HIV and the macrophages that can sequester HIV for long periods of time in tissues. If an anti-HIV element can be introduced into HSC, it will be passed along to all of the progeny of that HSC, ensuring the continuous, life-long production of HIV resistant cells. If this therapy were completely successful, this treatment would permanently protect the patient from HIV spread and no further treatments would be required. The NHGRI program has integrated several different lines of research into our HIV efforts. AIDS related malignancies as well as the potential safety of HSC gene therapy demands a thorough understanding of the consequences of vector insertion into the genome. NHGRI intramural researchers are comparing the integration sites of lentivirus and oncoretrovirus vectors in cultured cell systems. We have also built up an extensive library of viral integrations in CD4+ lymphocytes and are correlating these with changes in the expression of nearby genes. Examples of these include genes that regulate hematopoietic cell cycle progression. Successful modification of HSC to resist HIV infection requires efficient stem cell transduction and efficient expression of the anti-HIV gene product. NHGRI investigators are developing vectors pseudotyped with the FeLV-C envelope, which recognizes an abundant receptor on HSC to improve gene transfer. In the coming year, we will extend these studies to include pseudotyping lentivirus vectors that carry anti HIV genes. To express the anti-HIV gene products at high levels the gene silencing associated with current vectors must be suppressed. To combat silencing, NHGRI intramural investigators are developing and evaluating different virus vectors that contain barrier elements to prevent silencing, and evaluating their performance in mouse models. The combination of these three initiatives should significantly improve the prospects for successful HSC based AIDS gene therapy. It is anticipated that the results of these studies can be combined into a clinical trial for AIDS gene therapy in the near future.[unreadable] NHGRI has initiated a genetic approach to AIDS that takes full advantage of the strengths of the intramural NHGRI clinical and basic research programs. NHGRI clinical researchers are studying the development of T lymphocytes and the role that specific gene play in this process. Many of these genes are associated with known inherited Immunodeficiency syndromes. Ultimately, these studies will be extended to HIV infected cells to provide an understanding of how HIV deactivates the immune system. These studies are critical for determining which anti-HIV gene products to use as well as to improve the production of HIV vaccines. [unreadable] Finally, the NHGRI Social and Behavioral Research Branch program will initiate an effort to counsel and educate individuals with AIDS. The Genetic Counseling program has completed an extensive study of the most effective counseling techniques for families with inherited immune disorders. The NHGRI AIDS initiative will compare counseling approaches that have been shown to be effective in inherited immunodeficiency diseases with counseling for AIDS families. Such psychological studies are expected to reveal whether different approaches are necessary to help families cope with AIDS and its consequences.